tbuckley/cabot-search huggingface dataset:
Abstract 3948: DDX5 helicase resolves G-quadruplex and transactivates MYC expression
Authors: Guanhui Wu, Zheng Xing, Luying Chen, Elizabeth J. Tran, Danzhou Yang
Journal: Cancer Research (2023)

Abstract DDX5 (DEAD-box protein 5) plays an important role in cell proliferation, differentiation, and tumorigenesis. DDX5 is a founding member of the DEAD-box RNA helicase family and known as a non-processive RNA helicase. It acts as a transcriptional co-activator of many cancer-associated genes, such as MYC, however, the underlying molecular mechanism is unknown. MYC is one of the most critical oncogenes and has a DNA G-quadruplex in its proximal promoter region (MycG4) that functions as transcriptional silencer. Guanine-rich DNA and RNA sequences can form G-quadruplex, a non-canonical secondary structure. However, MycG4 is highly stable and its regulatory role in transcription requires active unfolding. Here, we report that DDX5 unfolds MycG4 with extreme efficiency, and thereby transactivates MYC expression. To understand the effects of DDX5 on MycG4, we characterized the unfolding of MycG4-DNA within the DDX5-MycG4 complex using DNA footprinting, FRET and CD spectroscopy. While DDX5 is known as a dsRNA helicase, our results showed that DDX5 is a highly active DNA G4-resolvase. Strikingly, MycG4 unfolding requires neither ATP hydrolysis nor extended loading of single-stranded flanking. Our protein-binding-ELISA experiments revealed specific and high-affinity binding of DDX5 to G4 structures regardless of whether the substrate is DNA or RNA. To elucidate the cellular functions of DDX5, we analyzed publicly available DDX5 ChIP-seq data and identified G-rich sequences in cancer cells as chromatin binding sites of DDX5. Moreover, our ChIP and Western Blot results showed that DDX5 is enriched at the MYC promoter and activates MYC transcription. Importantly, G-quadruplex interactive small molecules can inhibit the DDX5 interaction with the promoter MycG4 and DDX5-mediated transcriptional activation of the MYC gene. In addition, knock-down of DDX5 expression with DDX5-specific siRNA in cancer cells resulted in downregulation of MYC expression and sensitization to G4-interactive small molecules. In summary, we identified resolving DNA and RNA G-quadruplexes as novel function of DDX5. Our results establish that the MYC-transactivation by DDX5 is mediated through unfolding of the MYC promoter quadruplex and thereby establish a new molecular target to suppress MYC for cancer intervention. Citation Format: Guanhui Wu, Zheng Xing, Luying Chen, Elizabeth J. Tran, Danzhou Yang. DDX5 helicase resolves G-quadruplex and transactivates MYC expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3948.
Abstract 1362: Impact of chemotherapy on functional and biochemical characteristics of cancer-associated fibroblasts​
Authors: Zihan Xia, Olivier De Wever
Journal: Cancer Research (2023)

Abstract Cancer-associated fibroblasts (CAFs), as the major components of the tumor microenvironment (TME), have been extensively explored and are known to be involved in tumor biology, including growth, energy metabolism, immune regulation, invasion and metastasis. A large number of preclinical studies describe the functional and biochemical impact of commonly used chemotherapeutics, such as paclitaxel and oxaliplatinum, on cancer cells, but their effect on the phenotypical and biochemical changes of CAFs and their reciprocal impact on tumor progression are lacking. In our study, we used patient-derived breast and colorectal CAF to evaluate dose-response effects of paclitaxel and oxaliplatinum, respectively first-line chemotherapeutics in breast and colorectal cancer. We evaluated the damage responses of CAF and investigated changes in morphology, cell death, woundhealing migration, type I collagen contraction and invasion, cytokine and chemokine release, differential protein expression, and metabolic activity. In response to paracrine signals emerging from chemotherapy-treated CAF we investigated the impact on functional activity of macrophages, neutrophils and cancer cells. Our project could help us better understand and modulate the activity of CAFs, which might provide novel targets for the clinical treatment of cancer. Citation Format: Zihan Xia, Olivier De Wever. Impact of chemotherapy on functional and biochemical characteristics of cancer-associated fibroblasts​ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1362.
Abstract 6057: Association of liver cancer and chronic liver disease with urinary glyphosate and its metabolites in Thailand
Authors: Daxesh P. Patel, Benjarath Pupacdi, Siritida Rabibhadana, Leila Toulabi, Majda Haznadar, Bhavik Dalal, Mohammed Khan, Joshua Stone, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U. Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Anuradha Budhu, Chulabhorn Mahidol, Xin W. Wang, Frank J. Gonzalez, Mathuros Ruchirawat, Christopher A. Loffredo, Curtis C. Harris
Journal: Cancer Research (2023)

Abstract Background: Glyphosate, the primary weed-killing ingredient in Roundup®, is the most widely used herbicide worldwide. The World Health Organization’s International Agency for Research on Cancer (IARC) Monographs Program classified glyphosate is a probable human carcinogen (Group 2A), capable of causing human cancer under some circumstances. Methods: We analyzed urine specimens from 848 sequential patients with liver cancer and matched non-cancer controls from five different regional hospitals in Thailand. Gas chromatography electrospray ionization mass spectrometry (GC-ESI/MS) technique was used to measure glyphosate and its metabolites aminomethylphosphonic acid (AMPA) and phosphoric acid (PPA) to study their levels in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and chronic liver disease (CLD) in comparison to matched population controls. Findings: Significantly higher levels of glyphosate were found in CLD patients compared to cancer cases and population controls, while significantly elevated levels of both AMPA and PPA were observed in HCC and CLD patients. Glyphosate and its metabolites were also detected at low to moderately high levels in convenience samples of food products and drinking water. Interpretation: These results raise concern about the potential role of glyphosate in chronic human liver disease and cancer. Citation Format: Daxesh P. Patel, Benjarath Pupacdi, Siritida Rabibhadana, Leila Toulabi, Majda Haznadar, Bhavik Dalal, Mohammed Khan, Joshua Stone, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U. Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Anuradha Budhu, Chulabhorn Mahidol, Xin W. Wang, Frank J. Gonzalez, Mathuros Ruchirawat, Christopher A. Loffredo, Curtis C. Harris, TIGER-LC Consortium . Association of liver cancer and chronic liver disease with urinary glyphosate and its metabolites in Thailand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6057.
Abstract 6098: Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305
Authors: Ling Yin, Junjie Chen
Journal: Cancer Research (2023)

Abstract The first-generation PARP inhibitors (PARPi) olaparib, niraparib, talazoparib and rucaparib have been clinically approved for several cancers, like breast, ovarian and prostate, especially in BRCA-mutant tumors which are of homologous recombination repair (HRR)-deficiency. All PARPi both target PARP1 and PARP2, causing cancer cell deaths deficient in HRR. However, only inhibition of PARP1 is required for synthetic lethality in HRR-deficient cells. AZD5305 is a highly selective PARP1 inhibitor which has been used in clinical trials. In this study, we used the Toronto Knock Out Library version 3 (TKOv3), which contains 70948 gRNAs targeting 18,053 protein-coding genes to perform whole-genome CRISPR-Cas9 screens with three isogenic cell lines 293A, MCF10A, and Hela to uncover known and new high-confidence genes synthetic lethal interacted with AZD5305. MAGeCK and Drug Z were used to analyze the results and genes were ranked according to their drugZ scores. We identify that in all three cell lines, PARP1 was in the top hit in positive selection which proves the AZD5305 indeed a PARP1 inhibitor. Moreover, through a comprehensive and comparative analysis with the screen results of first generation PARPi olaparib, we reveal known and new essential genes which are proved to be a common mechanism for synthetic lethality. We identify the gene AUNIP (Aurora Kinase A and Ninein Interacting Protein), in the top hit from AZD5305 screen but not in olaparib screen, suggesting that AUNIP may be an additional target for synthetic lethality with PARP1 loss. Taken together, this screen reveals the potential molecular genes related with PARP1 inhibitor that can be further explored targeted and combined cancer therapy. Citation Format: Ling Yin, Junjie Chen. Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6098.
Abstract 4984: Integrated platform enables KRAS-targeted drugs discovery
Authors: Beibei Liu, an Li, Xiangyang Zuo, Jie Yang, Ruifeng Wang, Feifei Fan, Wenting Shi, Qingyang Gu
Journal: Cancer Research (2023)

Abstract The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS-MAPK pathway. Activating mutations in KRAS increase the ability for GTP-loading, making it difficult to displace, thus constitutively activate downstream MAPK pathway and promote cancer formation. Fortunately, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for KRAS inhibitor development efforts. These inhibitors, such as AMG510 and MRTX849, show promising results in patients with tumors harboring KRAS G12C mutation. While the approval of AMG510 was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors is unavoidable. Therefore, develop new drugs direct various KRAS mutants and combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors. To enable the discovery of novel KRAS inhibitors, we established a one-stop service platform, covering affinity detection of compounds to KRAS mutants, KRAS upstream and downstream protein-protein interaction detection, pathway activation detection, cell proliferation assay (2D/3D culture system), and in vivo efficacy evaluation in KRAS mutant xenograft models. Our platform provides assays on nearly all the current mainstream mutants of KRAS, such as G12C/G12D/G12R/G12S/G13D, and engineered Ba/F3 cell lines that harboring single or double KRAS mutation. In addition, we developed a panel of resistant models to KRAS G12C inhibitor that bringing a better understanding of the biological basis of drug resistance, and will serve as a new tool to optimize KRAS-G12C inhibitor regimens and combinatorial strategies. The comprehensive KRAS-targeted drug discovery platform is empowering new drug research and development. Citation Format: Beibei Liu, an Li, Xiangyang Zuo, Jie Yang, Ruifeng Wang, Feifei Fan, Wenting Shi, Qingyang Gu. Integrated platform enables KRAS-targeted drugs discovery. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4984.
Abstract 2793: Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate
Authors: Rong Shi, Shengchao Lin, Yu Zhang, Bing Li, Haiqing Hua, Yang Qiu
Journal: Cancer Research (2023)

Abstract Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, the preclinical pharmacokinetics (PK) characteristics of DB-1303 in cynomolgus monkeys is reported, and human PK exposure in a first in human study was predicted using population PK model with allometric scaling. Material and Methods: The PK parameters of DB-1303 were obtained from single PK and repeated TK studies in female and male cynomolgus monkeys. Concentrations of DB-1303 ADC, total antibody and released payload P1003 were measured using ELISA or LC-MS/MS. In a PK study, single dose of DB-1303 at 1, 3 and 10 mg/kg were determined in cynomolgus monkeys via IV infusion. In TK studies, cynomolgus monkeys were intravenously administered with DB-1303 at 50, 80 mg/kg once every 3 weeks for 2 repeated doses, or 10, 40, 80 mg/kg once every 3 weeks (Q3W) for 3 repeated doses followed by a 4-week recovery. A population PK model was developed based on the collective PK/TK data in monkeys. Results: The non-compartment analysis PK parameters of three analytes (DB-1303 ADC, total antibody and released payload P1003) are summarized following single and multiple doses of DB-1303 in cynomolgus monkeys. To predict the human PK for DB-1303, a target mediated drug disposition (TMDD) model was constructed, incorporating binding to serum HER2 and subsequent elimination of the complex into a standard 2-compartmental PK model. The 2-compartment linear parameters were scaled from cynomolgus monkey population PK parameters using allometric scaling exponents of 1 for volumes and 1 for clearance. The binding of DB-1303 to HER2 was incorporated into the model and assumed to be the same for HER2 ECD and transmembrane domain. The PK profiles for DB-1303 in human at the proposed doses in the first in human study are predicted. The safety margins from the monkey HNSTD for each proposed human dose are calculated. Conclusions: DB-1303 exhibited favorable PK characteristics of DB-1303 in cynomolgus monkeys, and is predicted to have large safety margins at the selected doses in the first in human study. At the time of presentation, the first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691). Citation Format: Rong Shi, Shengchao Lin, Yu Zhang, Bing Li, Haiqing Hua, Yang Qiu. Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2793.
Abstract 2829: Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma
Authors: Heng Jinghua, Li Enmin, Xu Liyan
Journal: Cancer Research (2023)

Abstract Purpose: The overall efficacy of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiotherapy (CCRT) resistance, which is dominated by radiotherapy. The aim of this study is to identify a radioresistant protein from proteomics and explore its molecular mechanism. Methods and Materials: The proteomic data of pre-treatment biopsy tissues of 18 ESCC patients with CCRT (complete response CR group, n = 8; incomplete response &amp;lt;CR group, n = 10) was collected, combined with PXD021701 to explore the radioresistant candidate. Subsequently, immunohistochemistry of 126 paraffin embedded biopsies was used for validation. The ESCC cell models with overexpression, knockdown or knockout of Acetyl-CoA Acetyltransferase 2 (ACAT2) were applied for exploring its effects on radioresistance using clonogenic assay underwent ionizing radiation (IR). ROS, C11-BODIPY, Fer-1 (ferrostatin inhibitor) and western blotting analysis were employed to reveal the potential mechanism ACAT2 triggered after IR. Results: Enrichment analysis of differentially expressed proteins (&amp;lt;CR vs. CR) showed that the pathways of CCRT resistance molecules in ESCC were related to lipid metabolism, while the sensitive ones were mainly aggregated to immunity pathways. ACAT2 was selected from proteomics and verified as a risk factor of overall survival and a radioresistant factor among ESCC patients with CCRT or radiotherapy by immunohistochemistry. ACAT2 overexpression conferred ESCC cell resistance to IR treatment, whereas the ACAT2 knockdown or knockout ones were sensitive to IR. ACAT2 knockout cells were prone to produce ROS and enhance lipid peroxidation after IR, which was rescued by Fer-1. ACAT2 knockout also inhibited GPX4 and phosphorylation of AKT-S473 site after IR. Conclusion: ACAT2 is negatively associated with the response of radiotherapy and prognosis of ESCC patients, suggesting ACAT2 as an effective therapy target to enhance radiosensitivity of ESCC. This work was supported by the National Natural Science Foundation of China (82273108 and 82173034), the Innovative Team Grant of Guangdong Department of Education (2021KCXTD005), the Science and Technology Special Fund project of Guangdong Province in 2021 (No. 210729156901797) and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG07B) Citation Format: Heng Jinghua, Li Enmin, Xu Liyan. Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2829.
Abstract 5346: Discovery of new targeted protein degraders using DNA-encoded chemistry
Authors: Anthony D. Keefe, Jeremy S. Disch, Jennifer Duffy, Esther C. Lee, Diana Gikunju, Betty Chan, Benjamin D. Levin, Michael I. Monteiro, Sarah A. Talcott, Anthony Lau, Fei Zhou, Anton Kozhushnyan, Neil E. Westlund, Patrick B. Mullins, Yan Yu, Moritz von Rechenberg, Junyi Zhang, Yelena Arnautova, Yanbin Liu, Ying Zhang, Andrew J. McRiner, Anna Kohlmann, Matthew A. Clark, John W. Cuozzo, Christelle Huguet, Shilpi Arora
Journal: Cancer Research (2023)

Abstract Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplars exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant that rapidly generated bispecific nanomolar degraders of ERα, with PROTACs inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization. Citation Format: Anthony D. Keefe, Jeremy S. Disch, Jennifer Duffy, Esther C. Lee, Diana Gikunju, Betty Chan, Benjamin D. Levin, Michael I. Monteiro, Sarah A. Talcott, Anthony Lau, Fei Zhou, Anton Kozhushnyan, Neil E. Westlund, Patrick B. Mullins, Yan Yu, Moritz von Rechenberg, Junyi Zhang, Yelena Arnautova, Yanbin Liu, Ying Zhang, Andrew J. McRiner, Anna Kohlmann, Matthew A. Clark, John W. Cuozzo, Christelle Huguet, Shilpi Arora. Discovery of new targeted protein degraders using DNA-encoded chemistry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5346.
Abstract 3843: Potent human ClpP protease agonists with anticancer properties bind the enzyme with improved structural complementarity and alter the mitochondrial N-terminome
Authors: Mark F. Mabanglo, Keith S. Wong, Marim M. Barghash, Lee M. Graves, Edwin J. Iwanowicz, Walid A. Houry
Journal: Cancer Research (2023)

Abstract The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate ROS-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small molecule agonists is a novel strategy in cancer therapy. Here, we synthesized novel imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular bases by which dysregulated ClpP affects cancer cell viability and proliferation. Citation Format: Mark F. Mabanglo, Keith S. Wong, Marim M. Barghash, Lee M. Graves, Edwin J. Iwanowicz, Walid A. Houry. Potent human ClpP protease agonists with anticancer properties bind the enzyme with improved structural complementarity and alter the mitochondrial N-terminome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3843.